Under normal physiological conditions, high density lipoprotein (HDL) plays an important role in regulating cellular cholesterol homeostasis and also possesses anti-inflammatory properties. Beneficial properties of HDL have been ascribed, in large part, to apolipoprotein A-I (apoA-I). Inflammation, however, can convert HDL into a dysfunctional lipoprotein particle that is depleted of apoA-I and enriched with acute phase proteins. Therapeutic approaches that increase plasma levels of functional HDL reduce ischemia-reperfusion (I/R) injury and other inflammatory disorders. Previous studies show that apoA-I mimetic peptides exert anti-inflammatory effects by increasing functional HDL levels and inhibiting monocyte/macrophage (M?) infiltration in tissues. In this regard, it was shown that the synthetic peptide 4F, which mimics functional properties of apoA-I, alters the metabolic profile of human monocyte-derived M?s, resulting in the adoption of an anti-inflammatory M2 phenotype. These responses were associated with up-regulation of genes that regulate mitochondrial respiration, resulting in an increase in oxidative phosphorylation and ATP formation. In this application, we present data showing that 4F reduces hepatocellular injury in a murine model of hepatic I/R injury. The protective response to 4F treatment is thought to be due to an increase in circulating levels of functional HDL. Specifically, we show that Kupffer cells (KCs), tissue resident M?s, adopt an anti-inflammatory phenotype. HDL may induce this response by increasing mitochondrial respiration and ATP formation, processes that support the induction of an anti-inflammatory wound healing response. Second, HDL may improve survival in hepatocytes via induction of autophagy, resulting in the clearance of damaged mitochondria and their replacement with new functional mitochondria. A mouse model of liver I/R will be used to test these hypotheses, and underlying mechanisms will be defined in cell culture systems.